JPH0257046B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to clathrate compounds, and particularly to novel clathrate compounds useful as sustained-release antibacterial agents. [Prior Art] In water systems such as cooling water systems of various factory facilities or pulp and paper manufacturing systems, slimes of various fungi or plants and animals such as those described below adhere, causing various problems. In the cooling water system, slime such as zooglare bacteria, algae, and filamentous fungi adheres to the cooling water system, causing a decrease in thermal efficiency, poor water flow, and induction of corrosion of metal materials. In the paper pulp manufacturing system, slime from bacteria, filamentous fungi, yeast, etc. is mainly generated during the paper making process, and this slime gets mixed in and adheres to the pulp slurry as foreign matter.
This not only reduces the quality of the product, but also causes various problems such as paper breakage and a significant drop in production efficiency. In particular, in recent years, there has been a trend to increase the amount of circulating water used in paper pulp manufacturing systems, and the problem caused by slime has become more important. Marine organisms such as seawater algae, seawater bacteria, mussels, and sea squirts adhere to the inside surfaces of the cooling water intakes and cooling pipes of thermal power plants, steel mills, and other factories that use seawater, resulting in a decline in their functionality. It is the cause of In addition, these attached organisms are peeled off by water pressure, flow velocity, etc., causing clogging of other parts such as the tubes and strainers of the heat exchanger, which obstructs the flow of seawater and reduces the functionality of the entire device. Conventionally, in order to prevent problems caused by slime, etc., it has been necessary to have a relatively simple treatment method.
Antibacterial agents (slime control agents) are commonly used because they are inexpensive. Particularly commonly used antibacterial agents include water-soluble antibacterial agents such as isothiazoline type compounds. Among these, in particular, 5-chloro- represented by the following a○ formula
2-Methyl-4-isothiazolin-3-one (hereinafter abbreviated as "CMI") has excellent antibacterial activity and is used as a slime control agent and antibacterial agent for various water systems such as cooling water systems, paper pulp, and swimming pools. It is widely used as an algaecide and fungicide. This CMI generally halogenates the β-thioketoamide in an inert organic ester solvent such as acetate. It is produced by a method in which β-substituted thiocyanoacrylamide or thiosulfate acrylamide is treated with an acid to obtain an isothiazolone, which is then further halogenated (Japanese Patent Publication No. 21240/1983). [Problems to be Solved by the Invention] However, in any of the above methods, it is not possible to selectively obtain only CMI, and as a by-product, the antibacterial activity shown by the following formula b 2-methyl-4-isothiazolin-3-one (hereinafter referred to as
It will be abbreviated as “MI”. ) can only be obtained. Moreover, with conventional technology, from the reaction product mixture
The reality is that it is not possible to selectively extract only CMI, and unavoidably, MI, which has inferior antibacterial activity, is used in a mixed state. On the other hand, although such CMI is an antibacterial agent having a certain degree of excellent antibacterial activity, it is extremely irritating to the skin and requires great care when handling.
Furthermore, when used in water, it reacts with organic substances (amines, reducing substances, etc.) in the water and loses its activity, making it difficult to maintain antibacterial activity for a long period of time. As described above, the water-soluble antibacterial agents that have been commonly used have extremely disadvantages in terms of handling, antibacterial effects, etc. due to toxicity, decreased antibacterial activity, and solubility in water. It was hot. [Means for Solving the Problems] The clathrate compound of the present invention is an clathrate compound that can solve the above-mentioned conventional problems and provide an excellent sustained-release antibacterial agent. ) to at least one compound selected from the group of compounds shown in parentheses. () 1,1,4,4-tetraphenyl-2-
Butyne-1,4-diol (hereinafter sometimes abbreviated as "TPB") () 9,10-di(4-methylphenyl)-9,
10-dihydroanthracene-9,10-diol (hereinafter sometimes abbreviated as "PhHA") () 1,1-di(4-hydroxyphenyl)
-Cyclohexane (hereinafter sometimes abbreviated as "PhCH") () 1,1,6,6-tetra(2,4-dimethylphenyl)-2,4-hexadiyne-1,
6-diol (hereinafter sometimes abbreviated as "TDPh") The present invention will be explained in detail below. The clathrate compound of the present invention consisting of CMI and the compounds shown in () to () above is as follows: (a), (b),
Manufactured using (c) as raw material. (a) Compounds of () to () in a solvent selected from water-soluble solvents such as methanol, ethanol, n-propanol, acetone, benzene, chloroform, esters such as ethyl acetate, and ethers such as dipropyl ether. A solution in which . (b) CMI. (c) A mixture containing CMI and impurities. That is, (a) and (b), or (a) and (c) are gradually added to water and reacted. As a result, the clathrate compound is precipitated by evaporating the solvent or leaving it for a while after the reaction, if necessary.
This precipitate is filtered and separated by a conventional method to obtain the desired clathrate compound. In this way, when producing the clathrate compound of the present invention, even if the raw CMI containing impurities such as by-products is used as it is, only the desired CMI can be selectively clathrated. This is extremely advantageous because it provides a clathrate compound with In addition, the solvent, manufacturing method, form of precipitate, etc. used in (a) above include the above () to () that include CMI.
differs slightly depending on the type of compound. When reacting the compound (TPB), benzene, chloroform, ethyl acetate, dipropyl ether, etc. are preferable as the solvent for dissolving it. After the reaction, by evaporating the solvent, the clathrate compound can be dissolved. precipitates as colorless transparent crystals. When reacting the compound (PhHA) in parentheses, chloroform, benzene, esters, and ethers are preferred as solvents for dissolving it.If the reaction is left overnight after the reaction, the clathrate compound forms a white plate-like substance. It precipitates as When reacting the compound (PhCH) in (), the solvent for dissolving it is methanol,
Ethanol and acetone are preferred, and after the reaction, the clathrate is precipitated as a green cloudy substance. When reacting the compound (TDPh), methanol, ethanol, and n-propanol are preferable as the solvent for dissolving it.
After the reaction, the clathrate is precipitated as a white turbidity. CMI, as a guest molecule, is selectively included in the above-mentioned compounds () to (), which are host molecules, and precipitates as an inclusion compound. The clathrate compound of the present invention obtained in this manner is generally obtained as an clathrate compound having the composition shown on the right side of each formula by the following reaction, although there are slight differences depending on the manufacturing conditions and the like. TPB+2CMI→TPB・(CMI) ₂ PhHA+2CMI→PhAH・(CMI) ₂ PhCH+CMI→PhCH・CMI TDPh+CMI→TDPh・CMI The clathrate compound of the present invention is usually a powdery solid and can be easily molded into tablets etc. It is. Furthermore, since CMI is included, the toxicity is low and it is easy to handle. The clathrate of the present invention is a guest molecule
Since CMI exhibits sustained release properties, it can be used as a sustained release antibacterial agent, and it can also be used to powderize CMI.
It is also useful for stabilization, concentration, etc. Furthermore,
Since the clathrate compound of the present invention is a reaction product with excellent selectivity between CMI and a specific host compound, it can also be used for separation and purification of CMI.
Its industrial utility is extremely high. When the clathrate compound of the present invention is used as a sustained-release antibacterial agent, the following methods may be used. Fill the column with this agent and pass the water to be treated. This drug is placed in a water-permeable, water-insoluble bag or cartridge, and used by immersing or floating it in a water system. Disperse this agent in molded or powdered form into an aqueous system and pour it out. Mix with paint, other resin, etc. and apply to water-based equipment surfaces, etc. Attach it to the surface of the protected object by an appropriate method. In this case, the sustained-release antibacterial agent may contain a clathrate compound of CMI and any one of the compounds () to () above, or each clathrate compound may contain two clathrate compounds. It may contain more than one species. [Operation] CMI becomes a solid state by forming an inclusion compound with the compounds () to () above.
Then, CMI gradually dissolves in water from the clathrate compound of the present invention. Also. CMI
By being included, its toxicity, skin irritation, etc. are reduced. Moreover, it also prevents the antibacterial activity from decreasing due to reaction with other substances during use. Furthermore, the clathrate compound of the present invention is useful for pulverizing, stabilizing, concentrating, etc. CMI, and since the compounds () to () above selectively clathrate CMI, it is useful for separating CMI, It is also useful for purification. [Examples] The present invention will be described in more detail below with reference to Examples, but the present invention is not limited to the following Examples unless the gist thereof is exceeded. Example 1 Production of clathrate compound Production of TPB/(CMI) ₂ : Add the above CMI and MI at a ratio of 3.4:1 to a TPB solution in which 1 g (2.56 x 10 ^-3 mol) of TPB is dissolved in 100 ml of benzene.
After adding 1 g (5.12 x 10 -3 mol) of a solution containing 1 g (5.12 x 10 ^-3 mol) and stirring, the mixture was allowed to stand at room temperature for 10 days to evaporate the benzene, and colorless and transparent crystals were precipitated.
This was filtered through filter paper to separate the precipitate and the solution. As a result of NMR analysis of the precipitates, the molar ratio of the precipitates was
TPB:CMI=1:2, the weight ratio was 56.6:43.4, and it was confirmed that MI was not included. Production of PhHA・(CMI) ₂ : 2 g (5.10×10 ^-3 mol) of PhHA was added to chloroform.
When 1.95 g (10.1 x 10 ^-3 mol) of the above solution containing CMI and MI at a ratio of 3.4:1 was added to a PhHA solution dissolved in 50 ml and stirred, white plate-like crystals were precipitated. This was filtered through filter paper to separate the precipitate and the solution. As a result of NMR analysis of the precipitates, the molar ratio of the precipitates was
PhHA:CMI=1:2, the weight ratio was 56.7:43.3, and it was confirmed that MI was not included. Production of PhCH/CMI: Add the above CMI and MI at a ratio of 3.4:1 to a PhCH solution in which 2 g (7.45 x 10 ^-3 mol) of PhCH is dissolved in 80 ml of benzene.
After adding and stirring 2.86 g (14.9 x 10 ^-3 mol) of a solution containing at a ratio of 10 - 3 mol, the mixture was allowed to stand overnight at room temperature, and colorless and transparent scaly crystals were precipitated at the benzene-water interface. The precipitate was taken out with tweezers, and the reaction solution was further allowed to stand overnight, and colorless and transparent scaly crystals were deposited again at the benzene-water interface. I took this out with tweezers. As a result of NMR analysis of the precipitates, the molar ratio of all precipitates was PhCH:CMI=1:1, and the weight ratio was 64.2:
35.8, and it was confirmed that MI was not included. Production of TDPh/ ^CMI : The above CMI and MI
When 7.3 g (38 x 10 ^-3 mol) of a solution containing 3.4:1 ratio was added and stirred, a white turbid substance precipitated. This precipitate was filtered through filter paper to separate the precipitate and the solution. As a result of NMR analysis of the precipitates, the molar ratio of the precipitates was
TDPh:CMI=1:1, the weight ratio was 77.9:22.1, and it was confirmed that MI was not included. CMI elution test Each clathrate compound and CMI alone were tested.
Each was placed in a 0.8μ membrane filter bag so that it weighed 0.1g in terms of CMI, immersed in 1 part of pure water, and after a certain period of time while stirring with a stirrer.
CMI concentration was measured and its change over time was investigated. The results are shown in Table 1.

[Table] As is clear from Table 1, when using CMI alone, CMI was eluted at the same time as the filter bag was immersed, but
In the clathrate compound according to the present invention, CMI is gradually eluted. Therefore, it is clear that when the clathrate compound of the present invention is used as an antibacterial agent, its antibacterial activity is maintained for a long time due to the sustained release effect in which the active ingredient CMI gradually elutes. [Effect of the invention] As detailed above, the clathrate compound of the present invention has
CMI is 1,1,4,4-tetraphenyl-2-
Butyne-1,4-diol; 9,10-di(3-methylphenyl)-9,10-dihydroanthracene-9,10-diol; 1,1-di(4-hydroxyphenyl)-cyclohexane or 1,1 ,6,
6-tetra(2,4-dimethylphenyl)-2,
It is clathrated with 4-hexadiyne-1,6-diol, and can be used for powdering, stabilizing, concentrating, manufacturing, etc. of CMI, and especially uses clathrated CMI as an active ingredient. As a sustained-release antibacterial agent, the active ingredient gradually dissolves into water, allowing it to maintain antibacterial activity for a long period of time. Since it is a solid, it can be molded into tablets and other forms, making it easy to handle. It reduces the toxicity and skin irritation of CMI, improving the working environment and improving overall performance. It has excellent effects such as preventing the active ingredient from reacting with other substances and reducing its antibacterial activity, making it extremely useful industrially.

Claims (1)

[Scope of Claims] 1. A clathrate compound of 5-chloro-2-methyl-4-isothiazolin-3-one and at least one compound selected from the group of compounds shown in () to () below. () 1,1,4,4-tetraphenyl-2-
Butyne-1,4-diol ()9,10-di(4-methylphenyl)-9,
10-dihydroanthracene-9,10-diol () 1,1-di(4-hydroxyphenyl)
-cyclohexane () 1,1,6,6-tetra(2,4-dimethylphenyl)-2,4-hexadiyne-1,
6-diol